In 1998, new HIV infections world-wide rose to nearly six million, while AIDS deaths increased to 2.5 million, more than were caused by either malaria or tuberculosis. 95% of AIDS cases occur in the developing world. In Zambia, a country in southern Africa, 25-30% of adults in urban areas are infected. In the US, drug-resistant HIV is observed with increasing frequency, and recent declines in HIV mortality have slowed. The US epidemic is increasingly one of underserved minority communities. In Alabama, more than 70% of new HIV infections in 1998 occurred in African-Americans. Understandably, the development of an effective HIV vaccine for global use has been declared the top priority of the NIH AIDS research program. The broad objective of this proposal is the establishment of an HIV Vaccine Trials Unit (HVTU) with a main site at the University of Alabama at Birmingham (UAB) and an international field site at the Zambia-UAB HIV Research Project (ZUHRP) in Lusaka. The specific aims of the proposed Alabama-Zambia HVTU are: 1) To perform domestic phase I and II clinical trials of candidate HIV vaccines in Alabama, The application describes: six years of AVEU experience at UAB performing phase I and II trials of HIV vaccines in over 225 vaccinated volunteers; and plans for HVTU volunteer recruitment, screening, enrollment, and retention, as well as safety monitoring, immune response analyses, protocol design, and CAB formation. 2) To perform international phase I and II clinical trials of candidate HIV vaccines in Zambia. Thirteen years of field experience in Rwanda and Zambia performing HIV natural history, intervention, and vaccine preparedness studies are described, as are plans for utilizing an existing ZUHRP cohort of HIV sero-discordant or concordant-negative couples in Lusaka for phase I/II HIV vaccine trials. 3) To prepare for future expansion to phase III clinical trials of candidate HIV vaccines in Zambia and Alabama. The Zambian cohort of > 500 discordant couples has a 9% HIV incidence despite voluntary testing and counseling, making this a powerful cohort for fixture efficacy trials. Recently, the Alabama clinic enrolled 125 higher-risk gay men in <5 months in the first US phase III trial. Plans for utilizing these cohorts and others are described.